Ischemic white matter injury and the consequent neuroimmune response can contribute to vascular cognitive impairment. The role of B cells in ischemic white matter injury is unclear. Here, we show that crosstalk between meningeal B cells and CNS-resident microglia exacerbates white matter injury and vascular cognitive impairment. The B cell population expands and is activated in the dura mater, correlating with worsened white matter damage and neuroinflammation, whereas B cell depletion alleviates myelin thinning and cognitive impairment following chronic cerebral hypoperfusion in adult male mice. Mechanistically, microglia recruit meningeal B cells via MIF-CD74/CXCR4 signaling, and B cells adopt an IgG-secreting phenotype. IgG-secreting B cells induce microglial ferroptosis through Fc gamma receptors. Our data show that B cells contribute to white matter injury and cognitive impairment. The role of B cells in vascular cognitive impairment is unclear. Here, the authors show a crosstalk between CNS border-associated B cells and parenchymal microglia, through MIFCD74/CXCR4 and IgG signaling, exacerbating white matter injury.

Ischemic white matter damage is a significant pathological feature of chronic cerebral hypoperfusion, leading to cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. In this study, we identify a causal association between genetically predicted extracellular signal-regulated kinase 5 (ERK5) expression and higher white matter hyperintensity volume through druggable target screening, suggesting its potential as a therapeutic target for white matter damage. Using different animal models of white matter damage, we show that Erk5 expression is significantly upregulated in microglia following both ischemic and demyelinating injury, correlating with the severity of white matter damage. Mechanistically, Erk5 exacerbates white matter damage by promoting microglial ferroptosis through the phosphorylation of nuclear factor of activated T-cells, cytoplasmic 4 (Nfatc4), which subsequently activates the expression of cleft lip and palate transmembrane protein 1-like protein (Clptm1l), a lipid scramblase involved in ferroptosis. Pharmacological and genetic inhibition of Erk5 in microglia effectively mitigates oxidative stress, lipid peroxidation, and ferroptosis, leading to a reduction in white matter damage and improved cognitive function. These findings underscore the potential of targeting the Erk5-Nfatc4-Clptm1l axis as a therapeutic strategy for ischemic white matter damage. Our study offers valuable insights into the molecular pathways driving white matter damage and provides a framework for the clinical translation of Erk5 inhibitors in the treatment of ischemic white matter damage.

Background Chronic cerebral hypoperfusion-induced white matter lesions are a major contributor to vascular cognitive impairment in aging, characterized by microglial activation and defective clearance of cholesterol-rich myelin debris. Perilipin-2 (PLIN2), a key lipid droplet (LD)-associated protein involved in myelin metabolism, has an undefined role in ischemic white matter injury. Methods Microglia-specific Plin2 knockout ( Plin2 ⁻/⁻ ) mice were subjected to bilateral common carotid artery stenosis (BCAS) to model cerebral hypoperfusion. Cognitive function, white matter integrity, and microglial phenotype were assessed. In parallel, integrated microglial transcriptomic and lipidomic analyses were performed to characterize inflammatory states and lipid metabolic profiles. Furthermore, the autophagy inhibitor chloroquine (CQ) was used in vivo and in vitro to test mechanistic dependence on autophagy. Results Plin2 deletion rescued BCAS-induced cognitive and motor deficits, attenuated white matter damage, and promoted remyelination. Plin2 ⁻/⁻ microglia exhibited enhanced clearance of myelin-derived LDs and a reduced pro-inflammatory state, driven by an upregulation of the autophagy-lysosomal pathway (lipophagy). Crucially, CQ treatment abolished these neuroprotective effects, as evidenced by re-induced LD accumulation, and reinstated inflammatory activation in Plin2 ⁻/⁻ mice and cultured microglia. Conclusion Microglial Plin2 deletion protects against hypoperfusion injury by enhancing LD clearance, reprogramming lipid metabolism, and suppressing neuroinflammation in an autophagy-dependent manner. Clinically, PLIN2 may represent a promising therapeutic target for ischemic white matter injury and vascular cognitive impairment.

Neuroinflammation, encompassing both innate and adaptive immune responses, plays a crucial role in ischemic stroke. Although B lymphocytes are central to adaptive immunity, their contributions to ischemic stroke remain poorly understood. Here, we demonstrated that B lymphocytes accumulate in ischemic lesions, forming germinal center-like structures at the later stage after stroke, which mainly depended on in situ proliferation. This accumulation correlated with worsened neuroinflammation and ischemic injury, whereas B cell depletion reduced chronic brain damage during stroke. Mechanistically, microglia recruited B cells into ischemic lesions through MIF-CD74/CXCR4 signaling during the early phase of stroke, while IFN-related pathways in B cells further drove neuroinflammation and brain injury. Targeting these pathways markedly alleviated cerebral ischemia and inflammation. Our findings shed light on the role of B lymphocytes in stroke pathology and suggest promising new avenues for therapeutic intervention.

Targeted protein degradation (TPD) has revolutionized drug discovery, with PROTACs leading the charge by catalytically eliminating disease-causing proteins. While conventional PROTACs degrade a single target, the complexity of diseases like cancer and neurodegeneration—marked by redundant and compensatory signaling networks—has spurred the rapid development of dual/multi-target PROTACs capable of simultaneously degrading two or more pathogenic proteins. This review systematically surveys recent advances (2023–2026) in this area, categorizing them into two classes: those targeting homologous proteins (e.g., CDKs, BCL-2/BCL-xL, HDACs, BAZ2A/BAZ2B) and those targeting distinct proteins across interconnected pathways (e.g., ERα/ARO, α-Syn/tau, BET/HDAC, PI3K/mTOR, FLT3/CHK1, CBP/BRD4, and others). For each, we critically analyze design strategies, structure–activity relationships, linker optimization, and E3 ligase selection. Despite remarkable progress—including the first dual degraders for non-kinase epigenetic regulators and protein aggregates—challenges persist in pharmacokinetics, off-target toxicity, and limited E3 ligase diversity. By consolidating key breakthroughs and practical SAR insights, this review provides a valuable resource for advancing next-generation multi-target degraders toward clinical translation for complex diseases.

Atherosclerosis (AS) has been shown to be an independent risk factor for vascular cognitive impairment (VCI), but the mechanisms remain unclear. Here, we found that AS circulating exosomes exacerbated ischemic white matter injury and VCI. Exosomes originating from macrophage-derived foam cells targeted microglia. Mechanistically, foam cell-derived exosomes transmitted redox imbalance, mitochondrial dysfunction, and metabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis. Anti-miR-101-3p or activation of Nrf2, both genetically and pharmacologically, could antagonize AS exosomes and ameliorate VCI. In conclusion, our findings reveal a distant connection between peripheral macrophages and brain microglia, which provides new insights and potential targets of AS-induced VCI.

Cognitive dysfunction poses a significant challenge in clinical practice, but currently available drugs mainly address symptoms and have limited effectiveness in treating cognitive dysfunction associated with various neurological disorders. Mendelian randomization (MR) and colocalization analyses were conducted to explore the causal associations between 4302 druggable genes with blood and brain cis-expression quantitative trait loci (eQTLs) and cognitive performance. The causal effects of candidate druggable genes on brain structure and neurological diseases were assessed to gain insights into the underlying mechanisms. Among over 4000 druggable genes, our study identified causal associations between 72 druggable genes (41 blood eQTLs and 31 brain eQTLs) and cognitive performance. Thirteen eQTLs (six in blood: ERBB3, SPEG, ATP2A1, GDF11, CYP2D6, GANAB; seven in brain: ERBB3, DPYD, TAB1, WNT4, CLCN2, PPM1B, CAMKV) were identified as candidate druggable genes for cognitive performance. Notably, both blood and brain eQTLs of ERBB3 were negatively associated with cognitive performance (blood: OR = 0.933, 95% CI 0.911-0.956, p-value = 9.69E-09; brain: OR = 0.782, 95% CI 0.718-0.852, p-value = 2.13E-08). Moreover, these candidate druggable genes exhibited causal effects on both brain structure and neurological diseases. Our integrative analysis provides genetic evidence supporting candidate therapeutic targets for improving cognitive performance and treating neurological diseases. Furthermore, it sheds light on the possible mechanisms by which these targets affect brain structures. This finding suggested that these identified druggable genes, particularly ERBB3 and CYP2D6, hold promise as potential drug targets for enhancing cognitive performance.

BACKGROUND:Chronic cerebral hypoperfusion-induced white matter lesions are an important cause of vascular cognitive impairment in aging life. TGF-β1 (transforming growth factor β1) is widely recognized as a multifunctional cytokine participating in numerous pathophysiological processes in the central nervous system. In this study, we aimed to evaluate the neuroprotective potentials of TGF-β1 in ischemic white matter lesions. METHODS:A mouse model of bilateral common carotid artery stenosis was established to imitate the ischemic white matter lesions. The agonist of the TGF-β1 pathway was continuously applied via intraperitoneal injection. The Morris water maze test and gait analysis system were used to assess the cognitive and gait disorders in modeling mice. The Luxol fast blue staining, immunofluorescence, and electron microscopy were conducted to determine the severity of demyelinating lesions, microglial activation, and dysfunction of the autophagy-lysosomal pathway in microglia. Furthermore, primary cultured microglia were exposed to extracted myelin debris and TGF-β1 in vitro to explore the underlying mechanisms. RESULTS:As evaluated by behavioral tests, TGF-β1 significantly alleviated the cognitive dysfunction and gait disorder in bilateral common carotid artery stenosis-modeling mice. The demyelinating lesion and remyelination process were also found to be highly improved by activation of the TGF-β1 pathway. The results of immunostaining and electron microscopy showed that TGF-β1 could ameliorate microglial activation and the dysfunction of lipid metabolism in myelin-engulfed microglia. Mechanistically, in primary cultured microglia exposed to myelin debris, administration of TGF-β1 notably mitigated the inflammatory response and accumulation of intracellular lipid droplets via promoting the lipid droplets degradation in the autophagy-lysosomal pathway, as quantified by flow cytometry, immunostaining, Western blot, etc. Yet, the application of autophagy inhibitor 3-methyladenine significantly reversed the above anti-inflammatory effects of TGF-β1. CONCLUSIONS:TGF-β1 relieved cognitive deficit, demyelinating lesions, and microglia-mediated neuroinflammation in bilateral common carotid artery stenosis modeling by reducing abnormal lipid droplet accumulation and dysfunction of the autophagy-lysosomal pathway in microglia. Clinically, staged activation of the TGF-β1 pathway may become a potential target and promising treatment for ischemic white matter lesions and vascular cognitive impairment.

BackgroundOvarian mucinous cystadenocarcinoma is a rare subtype of ovarian epithelial carcinoma that is resistant to platinum-based chemotherapy and has a poor prognosis, and there is no standard treatment plan for patients for whom multiline treatment has failed.Case presentationoma with FIGO stage IVB disease who was sequentially treated with paclitaxel liposomes+carboplatin, 5-Fu+CF+oxaliplatin, capecitabine+oxaliplatin, bevacizumab+FOLFOX4, S-1, and bevacizumab+oxaliplatin+raltitrexed chemotherapy. After the progression of the disease, a combination of short-course hypofractionated radiation therapy and immune checkpoint inhibitors was used. The radiotherapy target area was the metastatic lymph nodes in the right posterior part of the hepatic artery, with a radiation dose of 30 Gy/10 F. Camrelizumab, an immune checkpoint inhibitor, was administered intravenously every three weeks at a dose of 200 mg each time. The therapeutic effect was significant, with CA125 levels within the normal range. Metastatic lymph nodes disappeared from the abdominal cavity. The therapeutic effect achieved a complete response (CR). Currently, CA125 levels are within the normal range, and abdominal CT reveals no tumor recurrence or metastasis. The duration of response (DoR) reached over four years.ConclusionOvarian mucinous cystadenocarcinoma is a rare tumor with poor treatment efficacy and poor prognosis. Short-course hypofractionated radiation therapy combined with PD-1 inhibitors may be an effective and safe treatment strategy.

Concomitant inhibition of ataxia telangiectasia and Rad3-related protein (ATR) and poly ADP-ribose Polymerase (PARP) pathways is a promising strategy in cancer therapy, potentially expanding the clinical utility of ATR inhibitor (ATRi) and PARP inhibitor (PARPi). A novel series of ATR/PARP1 dual inhibitors is developed through the pharmacophore fusion of AZD6738 and Olaparib. Among them, B8 emerges as the most promising candidate, exhibiting potent ATR (IC50: 17.3 nM) and PARP1 (IC50: 0.38 nM) inhibition. B8 effectively reduced cell viability, induced apoptosis, and caused G2/M cell cycle arrest in TNBC cells. Additionally, B8 significantly impaired TNBC colony formation, migration, and invasion. Mechanistically, B8 induces DNA damage, evidenced by increased γH2AX levels. In in vivo studies, B8 suppressed tumor growth more effectively than the combination in MDA-MB-468 xenografted mice, with no significant body weight loss. B8 also enhanced γH2AX expression in tumor tissues. These findings confirm the synergistic effects of ATR/PARP1 co-inhibition and highlight the potential of this novel inhibitor class for TNBC therapy.

The 5-year survival rate for metastatic clear cell renal cell carcinoma (ccRCC) is only 8%. Although antiangiogenic therapy like axitinib is the first-line treatment, tumors often develop resistance rapidly. This study investigates the role of NUMB-like endocytic adaptor protein (NUMBL) in this resistance. We found that NUMBL expression is upregulated in axitinib-resistant ccRCC cells. Knocking down NUMBL in a resistant 769P cell line significantly reduced the axitinib IC50 from 218.3 μM to 113.2 μM, thereby restoring drug sensitivity. Mechanistically, NUMBL upregulates ubiquitin C-terminal hydrolase L1 (UCHL1). UCHL1 then interacts with and deubiquitinates matrix metalloproteinase 9 (MMP9), leading to MMP9 protein stabilization and increased expression. This cascade ultimately promotes vasculogenic mimicry (VM), a nonangiogenic vascularization process that contributes to axitinib resistance. Our research elucidates this novel NUMBL/UCHL1/MMP9 axis in driving VM-mediated resistance at molecular, cellular, tissue, and animal levels. By integrating the roles of NUMBL, VM, and deubiquitination, this work establishes a theoretical foundation for understanding axitinib resistance and provides new perspectives for improving ccRCC treatment efficacy.

Background Oxidative stress and microglial activation are critical pathomechanisms in ischemic white matter injury. Microglia, as resident immune cells in the brain, are the main cells undergoing oxidative stress response. However, the role and molecular mechanism of oxidative stress in microglia have not been clearly elucidated during white matter ischemia. Methods Extensive histological analysis of the corpus callosum was performed in BCAS mice at different time points to assess white matter injury, oxidative stress and microglial activation. Flow cytometric sorting and transcriptomic sequencing were combined to explore the underlying mechanisms regulating microglial oxidative stress and functional phenotypes. The expression of critical molecule in microglia was regulated using Cx3cr1CreER mice and clinical-stage drugs to assess its effect on white matter injury and cognitive function. Results Our study identified nuclear factor erythroid-2 related factor 2 (Nrf2) as a key transcription factor regulating oxidative stress and functional phenotype in microglia. Interestingly, we found that the sustained decrease in transiently upregulated expression of Nrf2 following chronic cerebral hypoperfusion resulted in abnormal microglial activation and white matter injury. In addition, high loads of myelin debris promoted lipid peroxidation and ferroptosis in microglia with diminished antioxidant function. Microglia with pharmacologically or genetically stimulated Nrf2 expression exhibited enhanced resistance to ferroptosis and pro-regenerative properties to myelination due to lipid and iron metabolism reprogramming. Conclusion Weakened Nrf2-mediated antioxidant responses in microglia induced metabolic disturbances and ferroptosis during chronic cerebral hypoperfusion. Targeted enhancement of Nrf2 expression in microglia may be a potential therapeutic strategy for ischemic white matter injury.

Large artery atherosclerosis (LAA) is a prevalent cause of acute ischemic stroke (AIS). Understanding the mechanisms linking atherosclerosis to stroke is essential for developing appropriate intervention strategies. Here, we found that the exosomal miRNA Novel-3 is selectively upregulated in the plasma of patients with LAA-AIS. Notably, Novel-3 was predominantly expressed in macrophage-derived foam cells, and its expression correlated with atherosclerotic plaque vulnerability in patients undergoing carotid endarterectomy. Exploring the function of Novel-3 in a mouse model of cerebral ischemia, we found that Novel-3 exacerbated ischemic injury and targeted microglia and macrophages expressing ionized calcium-binding adapter molecule 1 in peri-infarct regions. Mechanistically, Novel-3 increased ferroptosis and neuroinflammation by interacting with striatin (STRN) and downregulating the phosphoinositide 3-kinase-AKT-mechanistic target of rapamycin signaling pathway. Blocking Novel-3 activity or overexpressing STRN provided neuroprotection under ischemic conditions. Our findings suggest that exosomal Novel-3, which is primarily derived from macrophage-derived foam cells, targets microglia and macrophages in the brain to induce neuroinflammation and could serve as a potential therapeutic target for patients with stroke who have atherosclerosis.

The pharmacological mechanism of β-elemene in non-small cell lung cancer (NSCLC) remains poorly understood. In this study, we identified aldehyde dehydrogenase 3B2 (ALDH3B2) as a pivotal target for β-elemene’s anti-tumor effects in NSCLC by bioinformatic analysis. The overexpression of ALDH3B2 is specifically associated with the malignancy of NSCLC and the poor prognosis in patients with lung adenocarcinoma. Furthermore, we observed a positive correlation between ALDH3B2 levels and the sensitivity of cells to β-elemene. Additionally, we confirmed that β-elemene suppresses ALDH3B2 expression in PC-9 and NCI-H1373 cell lines. Notably, ALDH3B2 overexpression in NCI-H1373 cells resulted in enhanced migration, invasion, and a prominent epithelial-mesenchymal transition (EMT), which could be attenuated by β-elemene via inhibition of ALDH3B2 expression. Subsequent investigations demonstrated that ALDH3B2 overexpression upregulated ribosomal protein SA (RPSA) expression. β-elemene counteracted the upregulation of RPSA by suppressing ALDH3B2. Furthermore, knocking down of ALDH3B2 and β-elemene treatment significantly reduced the activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathways via suppression of RPSA. In summary, our research uncovers that in NSCLC, ALDH3B2 functions as an oncogenic protein, promoting tumor progression. Meanwhile, β-elemene inhibits EMT of NSCLC by inhibition of ALDH3B2/RPSA axis and subsequently downregulating AKT and ERK signaling pathways. Our study highlights the significant role of ALDH3B2 in the progression of NSCLC, signifying it as a potential pharmacodynamic biomarker for β-elemene. These findings enrich the understanding of anti-tumor pharmacological mechanism of β-elemene, and provides new theoretical and experimental foundations for its potential application in the treatment of NSCLC.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) accompanied by blood-brain barrier (BBB) disruption. Dysfunction in microglial lipid metabolism is believed to be closely associated with the neuropathology of NMOSD. However, there is limited evidence on the functional relevance of circulating lipids in CNS demyelination, cellular metabolism, and microglial function. Here, we found that serum low-density lipoprotein (LDL) was positively correlated with markers of neurological damage in NMOSD patients. In addition, we demonstrated in a mouse model of NMOSD that LDL penetrates the CNS through the leaky BBB, directly activating microglia. This activation leads to excessive phagocytosis of myelin debris, inhibition of lipid metabolism, and increased glycolysis, ultimately exacerbating myelin damage. We also found that therapeutic interventions aimed at reducing circulating LDL effectively reversed the lipid metabolic dysfunction in microglia and mitigated the demyelinating injury in NMOSD. These findings shed light on the molecular and cellular mechanisms underlying the positive correlation between serum LDL and neurological damage, highlighting the potential therapeutic target for lowering circulating lipids to alleviate the acute demyelinating injury in NMOSD.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.

Circulating miR-30c-2-3p has been closely related to vascular diseases, however, its role and underlying mechanisms in ischemic stroke remained unclear. Our study addressed this gap by observing elevated levels of exosomal miR-30c-2-3p in patients with acute ischemic stroke due to large artery atherosclerosis. Further investigation revealed that these exosomal miR-30c-2-3p primarily originated from macrophages within atherosclerotic plaques, exacerbating ischemic stroke by targeting microglia. Exosomes enriched with miR-30c-2-3p increased microglial inflammatory properties in vivo and aggravated neuroinflammation by inhibiting SMAD2. In summary, our findings revealed a novel mechanism whereby macrophage-derived foam cells within atherosclerotic plaques secrete exosomes with high levels of miR-30c-2-3p, thus aggravate brain damage during ischemic stroke, which serves as crucial link between the periphery and brain.

Polyadenosine diphosphate-ribose polymerase 7 (PARP7) acts as a suppressor of the type I interferon (IFN) signaling pathway via suppressing TANK-binding protein 1 (TBK1). Research study indicates that inhibition of PARP7 could potentially regulate tumor immunity. However, the effect of PARP7 inhibition on innate antiviral immunity in macrophages as well as the underlying mechanism have not been demonstrated else well. We report herein that PARP7 inhibitor clinical candidate RBN-2397 could augment type I interferon (IFN-I) production in macrophages by elevating retinoic acid-inducible gene I (RIG-I) and stimulator of interferon genes (STING) signaling pathways. Treatment with RBN-2397 leads to increased pattern recognition ligands-induced interferon-β production in primary bone marrow-derived macrophages (BMDM) and RAW264.7 cells. Additionally, RBN-2397 suppresses viral replication efficiency in macrophages infected by vesicular stomatitis virus (VSV) and amplifies the expression of interferon-stimulated chemokine genes (ISGs). Mechanistically, RBN-2397 promotes TBK1 phosphorylation, consequently leading to the amplified activation of RIG-I and STING signaling pathways. Furthermore, RBN-2397 enhances the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 induced by IFN-α/β and the expression of chemokine genes in macrophages in response to IFN stimulation. In vivo experiments demonstrated that RBN-2397 enhances innate antiviral immunity in mice infected with VSV, resulting in increased serum IFN-β levels, reduced viral loads, and alleviated pulmonary inflammatory responses of the VSV-infected mice. In conclusion, our findings highlight the potential of RBN-2397 as a promising antiviral therapeutic agent for enhancing the IFN-relative antiviral immune defense in host.